Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months

Abstract

We report orthotopic (life‐supporting) survival of genetically engineered porcine cardiac xenografts (with six gene modifications) for almost 9 months in baboon recipients. This work builds on our previously reported heterotopic cardiac xenograft (three gene modifications) survival up to 945 days with an anti‐CD40 monoclonal antibody‐based immunosuppression. In this current study, life‐supporting xenografts containing multiple human complement regulatory, thromboregulatory, and anti‐inflammatory proteins, in addition to growth hormone receptor knockout (KO) and carbohydrate antigen KOs, were transplanted in the baboons. Selective “multi‐gene” xenografts demonstrate survival greater than 8 months without the requirement of adjunctive medications and without evidence of abnormal xenograft thickness or rejection. These data demonstrate that selective “multi‐gene” modifications improve cardiac xenograft survival significantly and may be foundational for paving the way to bridge transplantation in humans.

The first clinical pig heart transplant: Was IVIg or pig cytomegalovirus detrimental to the outcome?

“…We fully recognize the immense effort put into the care of this patient by the Maryland team, and we applaud the willingness of the patient to undergo such an experimental procedure. months, 4,51 with these grafts being lost through antibody-mediated rejection. Although, in the absence of the problems associated with the 4 th xenoantigen, 5,11 the results in humans may be superior to those in NHPs, the outcome for a patient with a pig heart graft remains uncertain.…”

“…The Maryland team had obtained encouraging results from pig orthotopic heart transplantation in baboons 2–4 . Using essentially the same genetically‐engineered pigs (with 10 genetic modifications) and immunosuppressive regimen (based on blockade of the CD40/CD154 co‐stimulation pathway), one would have anticipated an equally encouraging result from their first clinical effort, particularly as the high prevalence of a positive cross‐match against “triple‐knock‐out” (TKO) pigs, likely associated with a putative “4 th xenoantigen” recognized by nonhuman primates (NHP), 5–8 is not observed in humans.…”

“…It should be noted that, in pig‐to‐NHP models of heart transplantation, the longest survivals reported to date have been less than 9 months, 4,51 with these grafts being lost through antibody‐mediated rejection. Although, in the absence of the problems associated with the 4 th xenoantigen, 5,11 the results in humans may be superior to those in NHPs, the outcome for a patient with a pig heart graft remains uncertain.…”

Expanding Donor Heart Utilization Through Machine Perfusion Technologies

“…These initial heart xenotransplants in non-human primates displayed a median survival of 298 days with an immunosuppression regime of MMF and anti-CD40 antibodies [45]. Similar studies using genetically modified heart xenografts demonstrated that the use of cold perfusion to preserve the donor heart reduced the incidence of perioperative cardiac xenograft dysfunction compared to SCS [40,46,47 [48] expanded the genetic modification of porcine donor hearts by using a maximum of nine modifications: insertions that regulate complement activation (hCD46, hDAF), coagulation (hTBM, hEPCR) and inflammation (hCD47, hHO-1), and deletions to minimize porcine cell antigenicity (GGTA1, B4GalNT2, CMAH) and cell growth (growth hormone receptor). In addition, cold perfusion was used for donor heart preservation in all but two donor porcine hearts.…”

Porcine Orthotopic Cardiac Xenotransplantation: The Role and Perspective of Anesthesiologists

“…17 Nevertheless, the heart appeared to develop overgrowth and thickening of the myocardium, with diastolic dysfunction resulting in ascites and heart failure. 18 The addition of growth hormone receptor knockout appeared to decrease this myocardial thickening, with diastolic dysfunction and extended survival past 9 months when added to genetic modifications of GTKO, b1,4-N-acetylgalactosyltransferase, hTBM, hCD46, hCD47, humanized heme oxygenase-1, decay-accelerating factor, and endothelial protein C receptor. 18 Anesthetic Care for Pig-to-Baboon Cardiac Xenotransplants…”